title: Regulation of the expression of death receptors and their ligands by melatonin in haematological cancer cell lines and in leukaemia cells from patients.
abstract: Incorporation of new therapeutic agents remains as a major challenge for treatment of patients with malignant haematological disorders. Melatonin is an indolamine without relevant side effects. It has been shown previously to exhibit synergism with several chemotherapeutic drugs in Ewing sarcoma cells by potentiating the extrinsic pathway of apoptosis. It also sensitizes human glioma cells against TRAIL by increasing DR5 expression. Here, we report the induction of cell death by melatonin in several human malignant haematological cell lines through the activation of the extrinsic pathway of apoptosis. Such activation was mediated by the increase in the expression of the death receptors Fas, DR4 and DR5 and their ligands Fas L and TRAIL, with a remarkable rise in the expression of Fas and Fas L. The cytotoxic effect and the increase in Fas and Fas L were dependent on Akt activation. Results were corroborated in blasts from bone marrow and peripheral blood of acute myeloid leukaemia patients, where melatonin induced cell death and increased both Fas and Fas L expressions. We conclude that melatonin may be considered as a potential antileukaemic agent and its therapeutic use, either alone or in combination with current chemotherapeutic drugs, should be taken into consideration for further research.
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Casado-Zapico
authors.forename: Vanesa
authors.initials: V
authors.lastname: Martín
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Santos
authors.forename: Jezabel
authors.initials: J
authors.lastname: Rodríguez-Blanco
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sánchez-Sánchez
authors.forename: Elisa
authors.initials: E
authors.lastname: Luño
authors.forename: Carlos
authors.initials: C
authors.lastname: Suárez
authors.forename: Juana M
authors.initials: JM
authors.lastname: García-Pedrero
authors.forename: Sofía T
authors.initials: ST
authors.lastname: Menendez
authors.forename: Isaac
authors.initials: I
authors.lastname: Antolín
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodriguez
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D008550:Melatonin / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D019014:fas Receptor; D053148:Caspase 3; D008550:Melatonin